LAUSR

Simple Summary Epstein–Barr virus (EBV) is the first discovered human tumor virus, which contributes to the oncogenesis of many human cancers. The ubiquitin–proteasome system is a key player during EBV-mediated oncogenesis and has been developed as a crucial therapeutic target for treatment. In this review, we briefly describe how EBV antigens can modulate the ubiquitin–proteasome system for targeted protein degradation and how they are regulated in the EBV life cycle to mediate oncogenesis. Additionally, the developed proteasome inhibitors are discussed for the treatment of EBV-associated cancers. Abstract Deregulation of the ubiquitin–proteasome system (UPS) plays a critical role in the development of numerous human cancers. Epstein–Barr virus (EBV), the first known human tumor virus, has evolved distinct molecular mechanisms to manipulate the ubiquitin–proteasome system, facilitate its successful infection, and drive opportunistic cancers. The interactions of EBV antigens with the ubiquitin–proteasome system can lead to oncogenesis through the targeting of cellular factors involved in proliferation. Recent studies highlight the central role of the ubiquitin–proteasome system in EBV infection. This review will summarize the versatile strategies in EBV-mediated oncogenesis that contribute to the development of specific therapeutic approaches to treat EBV-associated malignancies.